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  Consistent prediction of mutation effect on drug binding in HIV-1 protease using alchemical calculations.

Bastys, T., Gapsys, V., Doncheva, N. T., Kaiser, R., de Groot, B. L., & Kalinina, O. V. (2018). Consistent prediction of mutation effect on drug binding in HIV-1 protease using alchemical calculations. Journal of Chemical Theory and Computation, 14(7), 3397-3408. doi:10.1021/acs.jctc.7b01109.

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Item Permalink: http://hdl.handle.net/21.11116/0000-0001-6D15-E Version Permalink: http://hdl.handle.net/21.11116/0000-0003-304D-1
Genre: Journal Article

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Bastys, T., Author
Gapsys, V.1, Author              
Doncheva, N. T., Author
Kaiser, R., Author
de Groot, B. L.1, Author              
Kalinina, O. V., Author
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1Research Group of Computational Biomolecular Dynamics, MPI for biophysical chemistry, Max Planck Society, ou_578573              

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 Abstract: Despite of a large number of antiretroviral drugs targeting HIV-1 protease for inhibition, mutations in this protein during the course of patient treatment can render them inefficient. This emerging resistance inspired numerous computational studies of the HIV-1 protease aimed at predicting the effect of mutations on drug binding in terms of free binding energy $\Delta G$, as well as in mechanistic terms. In this study, we analyse ten different protease-inhibitor complexes carrying major resistance-associated mutations (RAMs) G48V, I50V, and L90M using molecular dynamics simulations. We demonstrate that alchemical free energy calculations can consistently predict the effect of mutations on drug binding. By explicitly probing different protonation states of the catalytic aspartic dyad, we reveal the importance of the correct choice of protonation state for the accuracy of the result. We also provide insight into how different mutations affect drug binding in their specific ways, with the unifying theme of how all of them affect the crucial for drug binding regions of the protease.

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Language(s): eng - English
 Dates: 2018-05-302018-07-10
 Publication Status: Published in print
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 Rev. Method: Peer
 Identifiers: DOI: 10.1021/acs.jctc.7b01109
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Title: Journal of Chemical Theory and Computation
Source Genre: Journal
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Pages: - Volume / Issue: 14 (7) Sequence Number: - Start / End Page: 3397 - 3408 Identifier: -